The rs1799895 single nucleotide polymorphism (SNP) is a non-synonymous base pair change in SOD3 that results in an arginine-to-glycine substitution (R213G) in extracellular superoxide dismutase protein (EC-SOD). This region is responsible for EC- SODs binding to extracellular matrix increases plasma levels 10-fold. The R213G SNP protects smokers from developing chronic obstructive pulmonary disease (COPD) and acute exacerbations of COPD. The goal of this proposal is to elucidate the mechanism by which the R213G protects the lung from tobacco smoke. To accomplish this aim, we have created a knock-in mouse with the identical SNP. Our methods will utilize more than a decade of experience studying the EC-SOD gene and COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the United States. The major risk factor is smoking; however, most smokers do not develop COPD. Although COPD is thought to be a genetic disease, there are only a few gene variants that have been repeatedly associated with COPD. One of these variants, the R213G single nucleotide polymorphism in the extracellular superoxide dismutase gene (SOD3), protects smokers from COPD and COPD exacerbations. This study will investigate the mechanisms by which R213G protects the lungs from cigarette-induced lung injury. This knowledge may help develop novel diagnostic tests and therapies to prevent and treat COPD.